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Ultra-small bispecific fusion protein augments tumor penetration and treatment efficacy for pancreatic cancer

Wang, Q.; Wang, J.; Yan, H.; Li, Z.; Wang, K.; Kang, F.; Tian, J.; Zhao, X.

2022-05-19 cancer biology
10.1101/2022.05.17.492287 bioRxiv
Show abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related deaths. Due to drugs low intrinsic anticancer activity and the unique physiological barrier of PDAC tumors, the once highly anticipated antibody-based pathway-targeted therapies have not achieved promising improvement in outcomes. Here, an ultra-small-sized bispecific fusion protein, termed Bi-fp50, that could largely enrich deep tumor tissue and effectively inhibit PDAC tumor growth was reported. The bispecific Bi-fp50 protein was constructed by a typical synthetic biology method that could efficiently target EGFR and VEGF of PDAC cells simultaneously in vitro and in vivo. For Bxpc3 and Aspc1 PDAC cells, the Bi-fp50 achieved a significant and synergistic therapeutic effect. Owing to the small size of only 50 kDa and the function of reducing the interstitial fluid pressure by vascular normalization, the Bi-fp50 showed enhanced penetration, considerable accumulation, and uniform distribution in tumor and subsequently led to effective inhibition of the growth of Bxpc3 cells-induced PDAC tumor in vivo. Furthermore, no noticeable side effect of Bi-fp50 was found in vitro and in vivo. This work demonstrates that the synthetic Bi-fp50 fusion protein could be used as a new effective pathway-specific targeted therapy for PDACs.

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